This invention relates to a kit and methods for reconstituting one or more dry powders with one or more liquids for use in a medical polymer delivery system. More particularly, this invention relates to a polymer kit and delivery system that prevents accidental blockage of the lumens of the delivery system due to mixing of precursor solutions within the device.
Hydrogels are materials that absorb solvents (such as water), undergo rapid swelling without discernible dissolution, and maintain three-dimensional networks capable of reversible deformation. See, e.g., Park, et al., Biodegradable Hydrogels for Drug Delivery, Technomic Pub. Co., Lancaster, Pa (1993).
Hydrogels may be uncrosslinked or crosslinked. Crosslinking involves mixing two components (e.g., solutions) to form a hydrogel. Crosslinkable solutions used to form hydrogels include those that may be used to form coatings on tissue, and may form physical crosslinks, chemical crosslinks, or both. Physical crosslinks may result from complexation, hydrogen bonding, desolvation, Van der Waals interactions, ionic bonding, etc., and may be initiated by mixing two components that are physically separated until combined in situ, or as a consequence of a prevalent condition in the physiological environment, such as temperature, pH, ionic strength, etc. Chemical crosslinking may be accomplished by any of a number of mechanisms, including free radical polymerization, condensation polymerization, anionic or cationic polymerization, step growth polymerization, etc.
For example, commonly owned U.S. patent application Ser. No. 09/390,046 describes a system for forming a hydrogel using two components that are separately introduced and mixed in situ from two syringes. Each of the two components is separately applied from a syringe into a respective lumen of a multi-lumen device that transports the components separately to the tissue site to be treated. The two components mix when released from the distal end of the device and combine in situ to form the desired hydrogel.
Several systems are known for reconstituting pharmaceutical or medicinal agents that need to be stored in a dry configuration and then are mixed with an aqueous solution prior to use, such as described in U.S. Pat. Nos. 4,458,733, 4,607,671, 4,759,756, and 4,328,802. For example, pre-filled syringes containing aqueous buffers are routinely used to reconstitute lyophilized drug or pharmaceutical powders in medical practice, such as described in U.S. Pat. No. 6,099,504, where the powders are stored dry for enhanced shelf life. In addition, the use of needle-less connectors are known for use in such systems, to minimize injuries, as described, for example, in U.S. Pat. Nos. 5,411,499, 5,688,254, 5,776,125, 5,846,233, 5,954,708, and 5,957,898. Several syringe configurations also are known in which a dry powder and a liquid component are separated by a barrier that allows intermixing prior to use, such as described in U.S. Pat. No. 5,171,220.
None of these systems, however, are suitable for use in dual component systems where two liquids are being used to simultaneously reconstitute two dry ingredients. In particular, the extension of single systems to dual systems is non-trivial because pre-configuration of the two liquid syringes can prevent the luer-locking mechanism from being engaged unless specific design features enable such movement. Additionally, there are unanticipated benefits of having a pre-configured system that arranges the two syringes in a rigid configuration relative to each other because such an arrangement obviates the need to separately level the liquid levels of the two syringes prior to introducing the liquids into the two dry powders. Accordingly, the quantities being thus introduced are uniform and assured to be in appropriate proportions.
Several dual component based medically useful polymer formulations are known in the art or are being developed. For example, fibrin sealants use a mixture of thrombin and fibrinogen based solutions to form fibrin glue and have numerous therapeutic uses. Similarly, several synthetic biomaterials based on polymers such as polyethylene glycol (PEG) are being developed. In general there is a need to store at least one if not both of the components of these dual component systems in a dry form that is reconstituted prior to use, for example in an operating room prior to surgery. However, this process for reconstitution can be time consuming and cumbersome. For example, the process for preparation of fibrin sealants involves more than a dozen steps to form a usable product and the process itself can take up to 45 minutes.
Where two liquids are used to reconstitute two dry powders, the liquids often are incompatible with the other dry powder and there is the possibility of accidentally mixing the wrong liquid with dry powder of the other liquid.
Moreover, additional applications of the two components from the syringes into the delivery device may be required to form a sufficient amount of polymer, such as a hydrogel. However, if the two components are applied to different lumens in subsequent applications such that portions of the two components from different applications mix inside the lumens, the polymer may form in the delivery device, thus causing the lumens to become blocked.
Additionally, it may be desirable to include one or more of a variety of drugs or bioactive agents in one or both of the polymer components, but not until shortly before it is desired to employ the components.
It would therefore be desirable to provide a simple, error-proof kit and system to rapidly prepare dual component systems.
It also would be desirable to provide methods and apparatus that prevents the lumens used to transport polymer components from becoming blocked by ensuring that the components do not become mixed inside the lumens of the delivery device during repeated applications of the components with the delivery device.
It further would be desirable to prevent blockage in lumens used to transport polymer components by providing a kit and delivery system having a key feature that prevents more than one type of polymer component from being applied inside a given lumen of the delivery device.
It still further would be desirable to provide a multi-component polymer kit and delivery system in which one or both components may include any one of a variety of drugs or biactive agents in either liquid or powder form.
In view of the foregoing, it is an object of the present invention to provide a simple, error-proof kit and system to rapidly prepare dual component medicinal polymer systems.
It is another object of the present invention to provide methods and apparatus that prevents the lumens used to transport polymer components from becoming blocked by ensuring that the components do not become mixed inside the lumens of the delivery device during repeated applications of the components with the delivery device.
It is a further object of the invention to prevent blockage in lumens used to transport polymer components by providing a kit and delivery system having a key feature that prevents more than one type of component from being applied inside a given lumen of the delivery device.
It is yet another object of the present invention to provide a multi-component polymer kit and delivery system in which one or both components may include any one of a variety of drugs or biactive agents in either liquid or powder form.
These and other objects of the invention are accomplished by providing a kit and delivery system having a key feature, and methods of use, that ensure proper mixing of the liquids and dry powders used to from the polymer components, and that prevent blockage of the delivery system lumens used to transport the components to the target site.
In a preferred embodiment, the two liquids are contained in pre-filled containers, such as syringes that are mounted in a clip that holds the syringes in a pre-determined configuration. A rigid member is removably coupled to the plungers of the syringes to allow simultaneous advancement of both plungers. Two substantially dry powders are disposed within containers, such as vials, and are also optionally mounted in a clip that is configured to allow for simultaneous attachment of both containers or vials of dry powders to be attached to the pre-filled syringes containing the liquids in a predetermined orientation. Needle-less connectors preferably are used to provide a continuous pathway allowing the liquids to flow from the pre-filled syringes into the respective vials containing the dry powders.
Once the double syringe holder is coupled to the double vial holder, the rigid member is advanced to simultaneously introduce the liquids into the respective vials containing the dry powders. The powders mix with the liquids to form the polymer components, which are then withdrawn from the vials into the syringes. The double syringe holder includes a key features that mates with a corresponding key feature of the double vial holder, thereby permitting the two elements to be coupled together with a predetermined orientation, so that the contents of each syringe can only be introduced into a corresponding one of the vials, but not the other vial. This ensures that each of the polymer components has the same orientation with respect to the syringes during repeated couplings of the syringes with the vials.
A delivery system is also provided that can be coupled to the double syringe holder with only one pre-determined orientation. Preferably, the delivery system includes multiple lumens. The double syringe holder is coupled to the delivery device so that the outlet of each syringe can be coupled to only a pre-selected one of the inlet ports of the delivery device. In this way each component is introduced into a separate lumen of the delivery device.
In accordance with the principles of the present invention, the delivery device also contains a key feature that permits the double syringe holder to be coupled in a unique configuration with a mating key feature of the delivery system. The key features therefore ensure that each of the polymer components is introduced through the same lumen upon repeated applications of the components to the delivery device. This in turn prevents accidental mixing of different components in the transport lumens, and thus prevents inadvertent blockage of the delivery device.
In addition, the kit and delivery system of the present invention facilitate use of one or more of a variety of drugs or bioactive agents as either the liquid or powder used in one or both of the polymer components.